Departments of Neurology and Neurological Sciences, Molecular and Cellular Physiology, Microbiology and Immunology, and Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, Neurosciences Graduate Program, Stanford University, Stanford, California 94305, and Center for Health Sciences, SRI International, Menlo Park, California 94025.
J Neurosci. 2013 Oct 2;33(40):16016-32. doi: 10.1523/JNEUROSCI.2203-13.2013.
Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP(1-4) receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. Ex vivo stimulation of peritoneal macrophages with LPS elicited proinflammatory responses that were dependent on EP2 signaling and that overlapped with in vivo plasma findings, suggesting that myeloid-lineage EP2 signaling is a major effector of innate immune responses. Conditional deletion of the EP2 receptor in myeloid lineage cells in Cd11bCre;EP2(lox/lox) mice attenuated plasma inflammatory responses and transmission of systemic inflammation to the brain was inhibited, with decreased hippocampal inflammatory gene expression and cerebral cortical levels of IL-6. Conditional deletion of EP2 significantly blunted microglial and astrocytic inflammatory responses to the neurotoxin MPTP and reduced striatal dopamine turnover. Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2(lox/lox) and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain.
前列腺素 E2（PGE2）是一种有效的脂质信号分子，通过激活下游 G 蛋白偶联的 EP（1-4）受体来调节炎症反应。在这里，我们通过其 E-前列腺素 2（EP2）受体在小鼠先天免疫反应中系统地和在中枢神经系统中研究了 PGE2 信号的细胞特异性体内功能。在体内，脂多糖（LPS）的全身给药导致血浆中细胞因子和趋化因子的广泛诱导，而 EP2 缺陷小鼠中的这种诱导明显减弱。用 LPS 对腹腔巨噬细胞进行离体刺激可引起依赖 EP2 信号的促炎反应，并且与体内血浆发现重叠，这表明髓样细胞系 EP2 信号是先天免疫反应的主要效应子。在 Cd11bCre;EP2(lox/lox) 小鼠中，条件性删除髓样细胞系中的 EP2 受体可减弱血浆炎症反应，并抑制全身炎症向大脑的传递，同时减少海马炎症基因表达和皮质 IL-6 水平。条件性删除 EP2 可显著减弱小胶质细胞和星形胶质细胞对神经毒素 MPTP 的炎症反应，并降低纹状体多巴胺的周转率。抑制小胶质细胞 EP2 信号还增加了黑质中多巴胺能（DA）神经元的数量，而与 MPTP 处理无关，这表明小胶质细胞 EP2 可能影响 DA 神经元的发育或存活。从成年 Cd11bCre;EP2(lox/lox) 和对照小鼠中分离的小胶质细胞的无偏微阵列分析表明，在删除小胶质细胞 EP2 受体后，炎症途径广泛下调。总的来说，这些数据表明巨噬细胞/小胶质细胞 EP2 信号在系统和大脑中的先天免疫反应中具有特定的促炎作用。
